ABSTRACT Streptococcus pneumoniae (Spn) is a major respiratory bacterial pathogen, asymptomatically carried (colonization) in the nasopharynx, by a significant proportion of the human population (children and adults). Colonization is a precursor to Spn disease (pneumonia, sinusitis, otitis media, sepsis, meningitis) which accounts for a significant disease burden in humans. Despite a decline in the overall Spn disease burden caused by currently available vaccines, Spn diseases continue to occur and remain a significant medical problem. Nasopharyngeal colonization is a precursor for Spn diseases, and co-infection with an influenza virus is a significant risk factor for the development of Spn disease. The influenza virus promotes damaging inflammation in the nasopharynx, which leads to bacterial outgrowth and dissemination of Spn bacteria to sterile tissues (lungs, blood) to establish disease. However, the mechanisms implicated in the damaging inflammation and consequent transition of Spn colonization into the disease, remain poorly understood. We developed an Spn-Influenza A Virus (IAV) co-infection model of Spn disease, by introducing IAV in Spn colonized mice. Our nasopharyngeal co-infection model mimics the natural pathogenesis of Spn involving the transition of Spn colonization to disease. Our preliminary data shows that the infection of Spn (serotype 6A) colonized mice with IAV elicits a robust IL-17A response that promotes hyper-inflammation in the NP, which leads to bacterial dissemination (lungs/blood) and the development of Spn disease. An antibody-mediated neutralization of IL-17A mitigated inflammation in the nasopharynx, results in a reduced Spn burden in the NP and blood with improved survival. Additionally, we show that innate lymphoid cells 3 (ILC3s) are a potential source of the pathogenic IL-17 response in our co-infection model of Spn disease. This data highlights the previously unrecognized role of the IL-17 response as a contributor to nasopharyngeal hyper-inflammation and the promotion of Spn disease in a co-infection setting with influenza virus. Based on our presented preliminary data, this 5-year research proposal hypothesizes that ?influenza-induced IL- 17 response leads to the development of a pro-inflammatory immune phenotype, epithelial inflammation, and compromised barrier response in the NP, resulting in the dissemination/invasion of Spn bacteria from the NP into the lungs/bloodstream to establish Spn disease?. This hypothesis will be tested in three structured aims that will describe the mechanisms operating at multiple levels from the generation of the pathogenic IL-17 response and the role of IL-17 receptor signaling in epithelial inflammation and airway-barrier integrity, leading to the development of Spn disease. The findings will be central to designing interventions for translational utility, in the future.